Mechanism of action of grape seed bioactive extract in relieving colitis

Grapes and grape byproducts (pomace, peel, and seeds) are rich in bioactive compounds. In IL-10-deficient mice, which are a model of colitis, polyphenols in grape extracts improved inflammatory bowel disease symptoms and intestinal epithelial structure.
——Bioactive compounds from dietary whole grape seed meal improved colonic inflammation via inhibition of MAPKs and NF-kB signaling in pigs with DSS induced colitis

1. Grape seed proanthocyanidin extract improves dextran sulfate sodium-induced colitis by improving intestinal barrier, reducing oxidative stress, and regulating inflammatory cytokines and intestinal microbiota

It is generally believed that grape seed proanthocyanidin extract (GSPE) has antioxidant and anti-inflammatory effects. It has been reported that dietary supplementation with GSPE can alleviate colitis symptoms in mice, but the related mechanism needs further exploration. In this study, Kangliang Sheng, Yongzhong Wang, and others from Anhui University explored how oral GSPE can improve colitis signs and reduce colitis-related inflammation.

C57BL/6 mice were treated with GSPE for 21 days. On the last 7 days of treatment, mice were injected with dextran sulfate sodium (DSS) dissolved in drinking water to induce experimental colitis. The study found that GSPE treatment improved DSS-induced colitis, as shown by a decrease in disease activity index (DAI) scores, pathological scores, and oxidative stress, as well as an increase in the mRNA levels of Zonula occludens-1 (ZO-1), occludin, and Claudin-1 in colonic tissues. Notably, GSPE treatment significantly downregulated the proinflammatory cytokines TNF-α and IL-1β in colonic tissues. GSPE treatment also reduced the mRNA level of NLR family pyrimidine domain-containing 3 (NLRP3) inflammasome in colonic tissues. In addition, analysis of 16S rRNA sequences showed that GSPE rebalanced the DSS-damaged intestinal microbiota, including a decrease in Bacteroidetes, Dunaliella, and Veillonella, an increase in Verrucomicrobia and Akkermansia, and an increase in the ratio of Firmicutes to Bacteroidetes.

In conclusion, GSPE supplementation alleviated DSS-induced colitis by maintaining the intestinal barrier and improving the microbial community by regulating inflammatory cytokines and oxidative stress. These results suggest that GSPE may be a new dietary strategy for the treatment of ulcerative colitis.

2. Protective effect of grape seed proanthocyanidins on acute colonic dysfunction induced by sodium dextran sulfate in vitro in humans

Purpose

In the case of intestinal dysfunction, anti-inflammatory and barrier protective properties have been attributed to the effects of proanthocyanidins, however, little information is available on the effects of these phytochemicals on human intestinal barrier integrity and immune responses. Therefore, Carlos González-Quilen, Raúl Beltrán-Debón, et al., from the University of Rovira-Vilgili, Spain, evaluated the protective properties of grape seed proanthocyanidins extract (GSPE) against acute colonic dysfunction induced by sodium dextran sulfate (DSS) in this study.

Methods

Human proximal and distal colon tissues from patients were treated with prophylactic GSPE (50 µg/mL or 200 µg/mL) for 30 min and then incubated with DSS (12%, m/V) for 1 h. Transperitoneal electrical resistance (TEER), permeability of fluorescently labeled dextran (FD4), and release of proinflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1β) of colonic tissues were measured.

Results

DSS reduced TEER in both proximal and distal colon (45%-52%); however, significantly increased FD4 permeation (4-fold) and TNF-α release (61%) were observed only in the proximal colon. Prophylactic GSPE treatment reduced DSS-induced TEER loss (20%-32%), FD4 permeation (66%-73%), and TNF-α release (22%-33%) in the proximal colon in a dose-dependent manner. The distal colon did not respond to the preventive treatment, but IL-1β release was reduced to below basal levels at the highest GSPE concentration.

Conclusion

The results of this study suggest that GSPE has a potential preventive effect on colonic dysfunction in humans. Further studies are needed to test whether GSPE can be used as a complementary treatment for colonic dysfunction associated with metabolic disorders and inflammatory bowel disease.

Ctrl. Krebs-Ringer bicarbonate (KRB) buffer alone (control); DSS. Acute colonic dysfunction induced by 12% dextran sulfate sodium in KRB buffer; GSPE-DSS. Grape seed proanthocyanidin extract (GSPE) incubation and DSS-induced acute colonic dysfunction.
Schematic diagram of the experimental scheme.

3. Bioactive compounds in grape seeds improve DSS-induced colonic inflammation in pigs by inhibiting MAPKs and NF-κB signaling

Highlights

• Grape seed diet (GSM) reduces diarrhea in DSS-treated piglets
• GSM reduces the expression of pro-inflammatory markers in the colon of piglets with colitis
• GSM inhibits the expression of MAPKs in the colon of piglets with DSS-induced colitis
• GSM reduces the expression of NF-κB in the colon of piglets with colitis
• GSM can be used as an alternative food supplement to reduce intestinal inflammation in inflammatory bowel disease (IBD)

The management of inflammatory bowel disease (IBD) symptoms focuses on finding new alternative strategies, including nutritional interventions, that can have a beneficial effect on intestinal inflammation. Using in vivo experimental methods combined with gene and protein analysis, Gina Cecilia Pistol et al. from the National Institute for Research and Development of Biological and Animal Nutrition in Romania studied the effects of an 8% grape seed diet (GSM) on inflammatory markers and signaling pathway molecules. The experiment used DSS-intervention pigs as an IBD animal model.

The results showed that DSS treatment induced extensive inflammation at the colon level and increased multiple pro-inflammatory molecules by activating the pro-inflammatory p38/ERK/JNK MAPK signaling cascade, followed by activation of NF-κB and other nuclear receptors. GSM effectively combats inflammatory diseases by inhibiting MAPKs, attenuating the expression of NF-κB genes and proteins, and reducing the production of pro-inflammatory cytokines and chemokines toward normal levels. Therefore, grape seed can be used as an alternative food supplement to reduce inflammation at the intestinal level.

Effects of different treatments on the synthesis of TNF-α, IL-1β, IL-6, and IL-8 in the colon.

Effects of experimental treatments on the gene expression of MAPKs in the colon.

4. Grape seed polyphenols improve dextran sulfate sodium-induced colitis by inhibiting inflammation and apoptosis

Background

Ulcerative colitis (UC) is an inflammatory bowel disease whose onset is usually progressive, with spontaneous remission periods and subsequent relapses. Grape seed polyphenols (GSP) are natural products extracted from grape seeds with strong anti-inflammatory properties.

Objectives

This study by Yunxia Wang, Rong Qi, and others from Peking University aimed to investigate whether GSP has an inhibitory effect on UC and its related mechanisms.

Methods

In this study, grape seeds were used as the research object. UC was induced by 2.5% dextran sulfate sodium (DSS), and GSP was administered orally to mice at different doses (500 mg/kg BW and 750 mg/kg BW per day). Body weight, diarrhea, and bloody stool were recorded daily to evaluate the disease activity index. Histological damage and inflammatory infiltration of colonic tissues were identified by hematoxylin-eosin staining and immunohistochemical staining. Real-time polymerase chain reaction was used to evaluate the mRNA expression of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α, and the expression of phosphorylated signal transducer and activator of transcription 3 (STAT3) was evaluated by Western blotting. Immunofluorescence was used to evaluate the apoptosis of intestinal epithelial cells (IECs).
Results

GSP can reduce the loss of intestinal epithelial cells, reduce weight loss, diarrhea, bloody stools, mucosal damage and inflammatory infiltration. GSP can also downregulate the mRNA expression of inflammatory cytokines IL-6, IL-1β and TNF-α, as well as the phosphorylation of STAT3, and improve the apoptosis of IECs.

Conclusion

This study shows that GSP has protective effects on cytokines IL-6, IL-1β and TNF-α, and can improve the apoptosis of IECs. GSP has a protective effect on DSS-induced UC, which may be achieved by inhibiting inflammation and apoptosis.

a. HE staining; b. Immunohistochemical staining of CD68; c. Histological score (combination of scores for mucosal damage and inflammatory cell infiltration). Magnifications are 20x and 100x.
GSP reduces pathological damage to the mucosa and inhibits the infiltration of inflammatory cells in the colon of DSS-induced UC mice.

a. IL-6; b. IL-1β; c. TNF-α; d. p-STAT3 and STAT3.
GSP inhibits the mRNA expression of inflammatory cytokines and the phosphorylation of STAT3.